ABSTRACT Dendritic cells (DCs) play critical roles in the regulation of anti-tumor immune responses. In both mice and humans, DCs consist of distinct subsets with intrinsic differences that lead to functional specialization in the generation of immunity. Compared to mice, little is known about the functional classification of human tissue- resident DCs, and how subset distribution is altered in disease. My laboratory has published pioneering studies on the identification and functional characterization of human DC subsets with respect to their control of cellular and humoral immunity. This application focuses on our recent discovery of a new human DC subset that is delineated by CD5 expression and that we discovered initially in human skin, blood and lymph nodes. CD5+ DCs are present in both mice and humans. They efficiently polarize T cells into helper and cytotoxic responses, and their number is reduced in melanoma affected compared to healthy tissue. Preliminary data using human DCs and pre-clinical mouse models are provided to demonstrate that CD5 is a critical molecule on DCs that sustains T cell activation and tumor rejection in vivo. Although the survival of advanced melanoma patients has been extended by interventions that enhance T cell activation, the response is limited to a minority of patients. Thus, we hypothesize that harnessing the CD5 costimulatory system on DCs will contribute towards the generation of a broad T cell response and immunological memory that is required to completely eliminate melanoma cells. To address this hypothesis, we will 1) harness novel murine models developed in our laboratory to define the requirement of CD5 on either DCs or T cells in tumor immunity, anti-tumor vaccination and in shaping response to checkpoint blockade therapy; 2) determine the molecular interactions underlying the activation and anti-tumor T responses by CD5+ DCs; 3) determine whether the distribution and the function of the CD5+ DCs is restored in patients with melanoma that respond to checkpoint blockade therapy. These studies will advance our understanding of a novel mechanism by which dendritic cells function to target cancer cells and will provide a rationale for harnessing CD5+ DC biology in a therapeutic setting.